Crystallization, as a major chemical separation and product preparation technology, is a key generic technology in the chemical, medicine, life, national defense and other fields, and creates huge economic benefits and social value. The control of the crystallization process determines the properties of the product and the separation efficiency, and is the key to the preparation of crystal products with ultra-high purity, specific crystal size and morphology.
Generally speaking, the crystallization process mainly includes three stages: (1) supersaturated state of the solution (or melt), (2) crystal nucleation in supersaturated and metastable systems, and (3) competition between crystal nucleation and growth. The accurate control of the crystallization process is based on the precise control of supersaturated degree of the system, ensured by the accurate judgement of crystal nucleation, and realized by the efficient control of a competition relationship between crystal nucleation and growth.
Currently, the control of the supersaturated degree of a crystallization system is mainly realized through single temperature control (such as cooling crystallization, melt crystallization, etc.) or concentration control (such as antisolvent crystallization, precipitation crystallization, etc.). However, the control interface is small and insufficient, which inevitably brings about low micromixing efficiency, uneven local supersaturated degree and uncontrollable burst nucleation caused by the difference in mass transfer rates, thereby seriously limiting the control accuracy of the crystallization process. Therefore, a new control technology is required to be developed to improve the controllability and adjustability of the crystallization process.
For example, cooling crystallization is a typical crystallization technology that produces the supersaturated degree by reducing solution temperature. In order to shorten the crystallization period, prevent the burst nucleation, effectively control crystal growth and obtain a crystal product with uniform size, a proper quantity of seed crystals with appropriate size are usually added into the solution, so that solutes can only grow on the surface of the seed crystals. It is necessary for the crystal seed to suspend in the solution system uniformly without agglomerate by selecting proper stirring; meanwhile, the secondary nucleation is avoided as much as possible. The temperature and the concentration of the solution must be precisely controlled throughout the crystallization process. Generally, desired seed crystals shall be the same crystals with relatively complete structures and components obtained in the same precipitation system, and high purity as well. However, the quantity, size, and pretreatment of crystal seed and the time of the addition have certain effects on final product quality. In the current crystal production, the addition of crystal seeds is based on the experience, and there is no theoretical and experimental basis for quantity and size of the adding seed crystals and the temperature of addition.
Chinese patents CN1736970A and CN102070625A mention that the crystal products that meet the requirements can be obtained by adding the seed crystals. However, in order to obtain the crystal products that meet the requirements, the quality and size of the seed crystals and the time of addition are strictly required in the control conditions. Once operating conditions are deviated, the quality of the crystal products will be affected. Therefore, it is very limited to produce different crystals with different sizes by using this method and it is also difficult to expand the production.
Antisolvent crystallization is a technology that generates the supersaturated degree by by gradually adding an antisolvent into the solution. The added antisolvent may be gas or liquid. In the process of antisolvent crystallization, dropping the antisolvent will result in high supersaturated degree at the addition point, and a large number of crystal nucleuses will be produced and agglomeration. Furthermore, the produced crystal nucleuses often contain mother liquid, which affects the quality of the crystal products. In the current industrial process, there are two ways of adding the antisolvent, namely, a dropwise stirring way and a novel jet way. In the dropwise stirring way, the diffusion rate of antisolvent droplets is limited, and the burst nucleation is easily happened because of the supersaturation level of the addition point is much higher than that of other places. At the same time, a large number of primary crystal nucleuses containing the mother liquid are produced, resulting in too wide crystal size distribution and the decrease of the product quality. Although the novel jet way improves the defect of uneven mixing to a certain extent, formed crystal structures have serious defects. In addition, high turbulence intensity will result in more crystal nucleation and low growth rate.
Chinese patents CN021152070.4, 200610165255.9, 201210594123.3 and 201310694016.2 mention that the drugs and biological macromolecular crystal products that meet the requirements can be prepared by antisolvent crystallization. However, the antisolvent crystallization mentioned in the patents is the dropwise stirring production process, which has poor control over the operation conditions and is difficult to expand the production; and the types of the crystals produced are also very limited. Moreover, in the patents, the optimization of the antisolvent crystallization is more about the improvement of the pretreatment of the crystallization solution, rather than the major production link of the antisolvent crystallization. Thus, the improvement of the quality of crystal products is very limited.
With the continuous development of membrane materials and science, the membrane has been widely used in various fields. Researchers have developed a variety of membrane separation processes for different industrial needs. In addition, membrane separation technologies are crossed, integrated and innovated with other technologies to give full play to the advantages of the membrane separation processes and make the industrial process more complete. The present invention establishes a continuous crystallization method and system based on control of a multistage membrane structure to obtain desired crystal products through the selection and modification of the membranes the control over the operation conditions, which uses membranes as heterogeneous nucleation surface, as well as the highly uniform dispersion control interfaces of temperature and concentration, and which gives full play to the advantages of the membrane materials and membrane modules in high precision control of the interface temperature and mass transfer process, The present invention is used for the preparation of medical, biological macromolecule and chemical products, and can greatly expand the application fields of cooling crystallization and antisolvent crystallization.